PL146074B1 - Method of obtaining novel optically pure tartaric monoesters with optically active alkanolamides and their salts - Google Patents

Abstract

For the analytical and preparative separation of the optical isomers of optically active alkanolamines into their optically pure antipodes a new resolution method is presented which involves an ester formation of the alkanolamines with optically pure and symmetrically O,O disubstituted (R,R)- or (S,S)-tartaric acids. The derivitization reactions are carried out in aprotic solvents and the primary and secondary functions are blocked via ion-pair formations with strong acids, e.g. dichloroacetic acid. The tartaric acid anhydrides are predominantly used as reagents but other ester formation methods are also practicable. The mixture of the diastereomeric alkanolamine tartaric acid monoesters are separable into their optically active and pure isomers by various chromotographic separation techniques, e.g. straight or reverse phase LC, but also by extraction methods e.g. Soxhlet extraction. The optically pure parent alkanolamine isomers can be obtained by ester hydrolysis, with high yield, from the optically pure fractions of the alkanolamine tartaric acid monoesters.

Description

The invention relates to a method for preparing new, optically pure tartaric acid monoesters with optically active alkanolamines and their salts with acids or bases. These new monoesters are particularly suitable for the easy preparation of optically pure alkanolamines. It is known that various aryl-, aryloxymethyl-, or heteroaryloxymethylethanolamines, including ethanolamines of the general formula 3, wherein A is a nitrophenyl, naphthyloxymethyl, or indolyloxymethyl group, or a substituted phenoxymethyl group of the formula 5, wherein R3 is a methoxyethyl group or an Acyl-NH- group, wherein Acyl is a lower alkanoyl radical with at most 4 carbon atoms or a dialkylcarbamoyl radical with 1 or 2 carbon atoms in each alkyl substituent, and R4 is a hydrogen atom or an acetyl radical, are valuable drugs. This group, apart from other pharmaceutically valuable alcoholamines, also includes known β-blocking substances, e.g. a substance called Nifenalol, in which the symbol A in formula 3 denotes a p-nitrophenyl group and R2 denotes an isopropyl radical, a substance called Propranolol, in which the symbol A in formula 3 denotes a 1-naphthyloxymethyl group and R2 denotes an isopropyl radical, a substance called Norpropranolol, in which the symbol A in formula 3 denotes a 1-naphthyloxymethyl group and R2 denotes a hydrogen atom, a substance called Pindolol, in which the symbol A in formula 3 denotes a 4-indolyloxymethyl group and R2 denotes an isopropyl radical, and the following β-blocking substances of formula 3, in which A denotes a group of formula 5, namely: a substance called Practolol, in which the symbol R3 denotes an acetylamino group, R4 denotes a hydrogen atom and R2 is an isopropyl radical, a substance called Metoprolol, in which the symbol R3 is a methoxyethyl group, R4 is a hydrogen atom and R2 is an isopropyl radical, a substance called Celiprolol, in which the symbol R3 is an N',N'-diethylureido group, R4 is an acetyl radical and R2 is a tertiary butyl radical, and a substance called Acetobutolol, in which the symbol R3 is an n-butyrylamino group, R4 is an acetyl radical and R2 is an isopropyl radical.2 146 074 All these compounds have a chiral center, so they occur as a racemate. It is known that the blocking activity on β-receptors is mainly attributed to the levorotatory enantiomer. For this reason, racemate resolution is of great importance. Racemate resolution has already been carried out for individual β-blocking substances, including those covered by the general formula III. This can be achieved by forming salts of these racemic β-blocking substances with optically active acids and separating the diastereomeric salt pair by fractional crystallization on the basis of their differing solubility properties. Such acids, which have already been used for the isolation of individual compounds of the general formula III from β-blocking substances, include, for example, camphorsulfonic acid (P. Newman, Optical Resolution Procedures for Chemical Compounds, Vol. I, Optical Resolution Information Center, New York, 19471), and (R,R)- or (S,S)-0,0-dibenzoyl- or (R,R)- or (S,S)-0,0-ditoluyl-tartaric acid (R. Howe, British patent specification GB-PS No. 1 069 343 and T. Leigh, Chem. Ind. London, 36, 1977). Although optically pure alkanolamines can be easily obtained from optically pure salts obtained in this way by alkalization, these methods are usually inconvenient because they often involve several crystallization steps to achieve sufficient resolution, and therefore quite expensive and laborious operations are necessary to prevent excessive losses of the substance. It has also been proposed to react racemic β-blocking substances, including individual compounds of formula 3, with optically pure reagents and convert them into diastereomeric products, which are then separated on the basis of their different properties into enantiomers and then split into optically pure β-blocking substances. Such optically pure reagents, e.g. in the case of Propranolol or Metoprolol, have been used as tert.-butoxycarbonyl-L-alanine or L-leucine anhydride [J. Hermansson and C. von Bahr, J. Chromatogr. 227 (1982) 113], N-trifluoroacetyl-S/-/-prolyl chloride [S. Caccia et al., J. Chromatogr. Science (1978) 543] or aralkyl isocyanates [W. Dieterle and W. Faigle, J. Chromatogr. 259 (1983) 311]. All these reagents are difficult to obtain and usually lead to products with an amide structure by reaction with the amine group of the alkanolamine. Apart from the fact that such amides can be cleaved only under quite harsh reaction conditions, which can lead to undesirable racemization, the site of formation of this derivative is also quite far removed from the chiral center of the alkanolamine, which results in smaller differences in the chemical and physical properties of these diastereomers than in the case of the formation of the 0-derivatives. It has been surprisingly found that it is possible to separate alkanolamines of formula 3 into optically pure isomers by a method combining ease of procedure with good separation results and carried out without tedious operations to products of high optical purity. This goal can be achieved when the unexpectedly very different chemical and physical properties of monoesters of these alkanolamines of formula 3 with specific, optically active disubstituents (R,R)- or (S,S)-tartaric acids of the general formula 4, wherein R5 is a straight-chain or branched-chain alkyl radical with 1-4 carbon atoms, a benzyl radical, an optionally chlorine-substituted straight-chain or branched-chain alkanoyl radical with 1-5 carbon atoms, a phenylacetyl, benzoyl, toluoyl or β,β-dichlorovinyl radical. A method for preparing new, optically pure tartaric acid monoesters with optically active alkanolamines of the general formula 1, wherein A is a nitrophenyl, naphthyloxymethyl or indolyloxymethyl group or a substituted phenoxymethyl group of the formula 5, wherein R3 is a methoxyethyl group or an Acyl-NH- group, wherein Acyl is a lower alkanoyl radical with at most 4 carbon atoms or a dialkylcarbamoyl radical with 1 or 2 carbon atoms in each alkyl substituent, and R4 is a hydrogen atom or an acetyl radical, and further wherein R2 is a hydrogen atom or a branched alkyl radical with 3 or 4 carbon atoms, and R1 is a radical of disubstituted (R,R)- or (S,S)-tartaric acid of the general formula 2, wherein R5 is a straight-chain or branched-chain alkyl radical with 1-4 carbon atoms, a benzyl radical, an optionally chlorine-substituted straight-chain or branched alkanoyl radical with 1-5 carbon atoms, a phenylacetyl, benzoyl, toluoyl or β,β-dichlorovinyl radical, and their salts with acids or bases, according to the invention, consists in that the mixture of enantiomers of the general formula 3, in which A and R2 have the above-mentioned meaning, is reacted in the melt or in an aprotic solvent with disubstituted (R,R)- or (S,S)-tartaric acid of the general formula 4, wherein R5 has the meaning given above, or with its anhydride, provided that the reaction with the free acid is carried out in the presence of a condensing agent, after which the resulting mixture of pairs of enantiomers of tartaric acid monoesters of the formula 1 is isolated, and then the resulting racemic mixture is separated into enantiomers, which are optionally converted into salts. Due to their strongly different chemical and physical properties, tartaric acid monoesters of the formula 1 can be easily separated into optically pure compounds, and a high optical purity can be achieved without tedious purification operations. Tartaric acids in which the alkyl radical contains 1-5 carbon atoms, preferably 1-4 carbon atoms, have proven particularly suitable as dialkyltartaric acids. Methyl, ethyl, and tert.-butyl radicals are particularly preferred. Dibenzyl tartaric acid is also preferably used. The alkanoyl radical in dialkanoyltartaric acids may be substituted with halogen, with the trichloroacetyl radical being a particular example. Unsubstituted alkanoyl radicals with 1-4 carbon atoms are preferred, with the acetyl radical being particularly preferred. Also suitable are the phenylacetyl, benzoyl or toluoyl radicals, with the λ,β-dichlorovinyl radical being particularly noteworthy. Due to their good separability, tartaric acid monoesters of formula 1 should be mentioned in particular, where A is a naphthyloxymethyl group and R2 is an isopropyl radical or a hydrogen atom, and also such tartaric acid monoesters of formula 1, where A is a group of formula 5, where R3 is a (C2H5)2N-CO-NH- group, and R4 is an acetyl radical, and R2 is a tert.-butyl radical, or where R3 is a methoxyethyl group, and R4 is a hydrogen atom, and R2 is an isopropyl radical. Furthermore, tartaric acid monoesters of formula 1, where A is a group p-nitrophenyl, and R2 is an isopropyl radical. Condensing agents for the reaction of free acids include, for example, carbodiimides, such as dicyclohexylcarbodiimide, p-toluenesulfonyl chloride, trifluoroacetic anhydride, sulfuryl chloride, a mixture of dimethylformamide and thionyl chloride, alumina, and molecular sieves. Since the amino group in the compounds of formula III is primary or secondary, it is also possible to react tartaric acid of formula IV or its anhydride with an amino group and form an amide. Surprisingly, however, in the reaction carried out in the process according to the invention, diastereomeric O-derivatives are preferably formed, while N-derivatives or disubstituted derivatives are formed only as by-products. These O-derivatives can be separated from the undesired N-derivatives by precipitation. However, it is advisable to protect the amino group for the duration of the reaction using protecting groups known for amino groups, which can be cleaved by saponification or hydrogenation. It is particularly advantageous to protect the amino group by forming a salt with a strong inorganic or organic acid that forms an ion pair with the amino group, which only slightly dissociates under esterification conditions. After esterification, this acid can be liberated by alkalization, for example, by treating the resulting ester with a weak base, e.g., aqueous NaHCO solution, or an amine. It is also possible to separate the acid protecting the amino group only after separating the tartaric acid monoester of formula 1 into optically pure esters. Sulfonic and halocarboxylic acids are organic acids that are ideally suited for protecting the amino group, while mineral acids are primarily suitable as inorganic acids. Preferably, toluenesulfonic acid, trichloroacetic acid, trifluoroacetic acid, or hydrochloric acid are used. A preferred embodiment of the process according to the invention is the reaction of tartaric anhydride of formula 4 with compounds of formula 3 in an anhydrous aprotic solvent at a temperature of 5-150°C. The temperature, depending on the solvent and reagents used, is advantageously maintained in the range from room temperature to 90°C, preferably in the range of 40-90°C. The acid anhydrides of formula 4 are used equimolar or in excess. The reaction is generally carried out within 2-36 hours.4 146 074 Aprotic solvents preferably include dichloromethane, 1,2-dichloroethane, acetone, acetonitrile, toluene, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or N-methylpyrrolidone-2. The solvents are used in the anhydrous state. Water, which may be introduced into the reaction medium via reagents, e.g., p-toluenesulfonic acid containing water of crystallization, is suitably removed before the reaction, e.g., by distillation. The mixture of diastereomeric tartaric acid monoesters of formula 1 thus obtained can be crystallized from an aqueous medium, preferably at a pH of 0 to 9, after removing the solvent, preferably by evaporation. Separation of these monoesters by extraction with organic solvents, preferably dichloromethane or dichloroethane, and subsequent distillation of the solvent is also possible. If the amino group in compounds of formula 3 is protected with acids, the acid from the dry reaction mixture is deliberately removed by adding an aqueous solution of a weak base. These acids can also be removed by treating solutions of tartaric acid esters with aqueous alkali solutions. Due to their acidic and basic groups, the diastereomeric esters of formula 1 thus obtained exist as zwitterionic compounds or as internal salts. They can be converted into acid addition salts by adding acids or into carboxyl salts by adding bases. From the resulting diastereomeric mixture of esters of formula I, optically pure esters of formula I can be obtained by separation on the basis of their different physical and chemical properties, wherein selective crystallization or extraction with an organic solvent and chromatographic separation are suitable. Suitable solvents from which fractional crystallization is possible include chlorohydrocarbons, ketones such as acetone, ethers, esters, secondary and tertiary alcohols such as isopropanol, water or aqueous buffer solutions. Usually, after 1-4 crystallization procedures, optically pure tartaric acid esters of formula 1 are obtained. However, extraction or chromatographic separation is preferably used for separation. For extraction, solvents are selected in which the esters of formula 1 do not undergo solvolysis or only slowly undergo solvolysis. Such solvents include chlorinated hydrocarbons, ketones, ethers, esters, secondary and tertiary alcohols, water or aqueous buffer solutions, with acetone, dichloromethane, dichloroethane, chloroform, ethyl acetate, cyclohexane-toluene, tetrahydrofuran, dioxane, ethyl ether, alkali metal phosphate or ammonium phosphate buffer solutions being preferred. Suitable chromatographic separation methods include thin layer chromatography, column chromatography and high-pressure liquid chromatography. Adsorption chromatography on silica gel or alumina columns using organic eluents such as acetone, isopropanol, dichloromethane, cyclohexane or toluene is preferred, with acetone/isopropanol being particularly preferred as eluent. Reverse-phase high-pressure liquid chromatography is also preferred, for example, with a reversed phase (RP 18) as the stationary phase. In the latter case, acidic buffer substances mixed with methanol or acetonitrile can be used as the mobile phase. In liquid chromatography (LC or HPLC), the separation of substances is achieved on the basis of different chemical-physical interactions within a three-compartment system: the substances to be separated, the stationary phase, and the mobile phase. In the reversed-phase system, the separation of a mixture is based, for example, on the different lipophilicity of the substances to the mobile and stationary phases, which is described by different partition coefficients. Under constant isocratic and isothermal conditions (a defined stationary phase, e.g., RP 18, and a defined mobile phase, e.g., a defined methanol-buffer mixture), the retention time of a substance is described over its total retention time. This depends on various column parameters and the mobile phase flow rate. To obtain a largely independent description of the behavior of a substance in a chromatographic system, the capacity coefficient k'i is formulated according to the equation given below: 146 074 5 kt tri-to i ? where i denotes substance i, tn denotes the total retention time of substance i, and t0 denotes the idle time of a substance not retarded in the same chromatographic system. To easily describe the behavior of two substances in one and the same chromatographic system, the concept of relative retention or, in other words, the alpha selectivity coefficient is defined, which gives the ability to separate a mixture of substances i-j according to the following equation: alfaij= -L k'i (substance j is retarded longer than substance i). High alpha values therefore indicate very selective separation of a specific mixture of substances, which in the examples given below each time constitute a diastereomeric pair of isomers. The k' and alpha values are therefore physicochemical quantities that are substance-specific and characteristic for a given chromatographic system (stationary phase in combination with a specific mobile phase). The above-mentioned criteria apply in a similar way to adsorption chromatography (cf. Chromatogr. Trennmethoden, G. Schwendt, Georg Thieme Verlag Stuttgart, 1979). The optically pure tartaric acid monoesters of formula I obtained in this way are extremely suitable as starting materials for the preparation of optically pure forms of the free alkanolamines of formula III, since they can be solvolytically cleaved under mild conditions. This cleavage is usually carried out at a temperature of -10°C to 40°C under acidic or basic conditions, for example with a 0.1-1N aqueous hydrochloric acid solution or with a 0.1-1N aqueous NaOH solution, or by transesterification, for example in methanol. For example, the hydrolytic cleavage of (R,R)-0,0-diacetyltartaric acid monoester and (R)-propranolol takes place by reaction with a methanolic NaOH solution at room temperature, the reaction lasting for 1 hour. Pure (R)-( + )-Propranolol is obtained with a rotation [α]d20 - + 8.33° (c = 1.0 in 95% ethanol) and an optical purity of 98% in a yield of 88%. It is also possible, for example, from the monoester of (R,R)-0,0-diacetyltartaric acid and (S)-Propranolol by treatment with a methanolic solution of hydrochloric acid for 24 hours at room temperature to obtain S-Propranolol with an optical purity of over 98% in a yield of 85% of theory and a rotation [α]d20 = -8.32° (c + 1.0 in 95% ethanol). Another possibility for preparing optically pure alkanolamines of the formula III consists in subjecting a mixture of diastereomeric tartaric acid monoesters of the formula I to stereospecific hydrolysis under controlled pH conditions or to stereospecific enzymatic hydrolysis. However, the route by separation of optically pure tartaric acid monoesters of the formula I is preferred. The following examples further illustrate the process according to the invention, with Examples I-III and XVI relating to the preparation of a mixture of diastereomeric compounds of the formula I. Example I 25.9 g (0.1 mol) of anhydrous basic (R,S)-propranolol are dissolved in 20.0 g (0.105 mol) of p-toluenesulfonic acid. H2O in 300 ml of 1,2-dichloroethane at room temperature, and the water of crystallization from the toluenesulfonic acid was removed by distillation. To the filtered solution was added 32.4 g (0.15 mol) of (R,R)-( + )-0,0-diacetyltartaric anhydride at room temperature, and the mixture was stirred under reflux at about 80°C for 24 hours. After removing the solvent in vacuo, the solid residue was taken up in 52% aqueous NaHCO3 solution until dissolved (approximately 200 ml) and then acidified with 1N hydrochloric acid to a pH of 2.5. A mixture of isomers of the diastereomeric monoester of (R,R)-0,0-diacetyltartaric acid and (R,S)-propanolol is precipitated or extracted three times with 100 ml of CH2Cl2 each. After removing the extractant, a residue is obtained (38 g, yield 80% of theory), which is crystallized in acetone. The above procedure can also be carried out under exactly the same conditions with (S,S)-(-)-0,0-diacetyltartaric anhydride as the reagent, and the corresponding mixture of isomers is also obtained in a yield of 80% of theory. Example II. 1.81 g (7 mmol) of anhydrous, basic (R,S)-propranolor was dissolved in 20 ml of dichloromethane and treated at room temperature with 3.02 g (14 mmol) of (R,R)-(+)-0,0-diacetyltartaric anhydride and stirred for 48 hours at room temperature. After removing the solvent in vacuo, the residue was treated with a solution of 16 mmol of NaHCO3 in 50 ml of water while stirring at room temperature, forming a crystalline precipitate. This precipitate was filtered off and washed with water, yielding the pure (R,R)-0,0-diacetyltartaric acid monoester of (S)-propranolor, which, upon hydrolysis, yielded optically pure (more than 98%) (S)-(-)-propranolol. The solution contains a diastereomeric mixture of (R,R)-0,0-diacetyltartaric acid monoester with (R)- and (S)-propranolor, which can be separated into enantiomers. 0.7 g (42% of theory) of (R,R)-0,0-diacetyltartaric acid monoester with (S)-propranolor is obtained. Example 3 2.34 g (10 mmol) of (R,R)-0,0-diacetyltartaric acid are suspended in 15 ml of dichloromethane and treated with 1.72 g (10 mmol) of anhydrous toluenesulfonic acid. A solution of 1.3 g (5 mmol) of (R,S)-Propranolor in 10 ml of dichloromethane was added dropwise with stirring, followed by a solution of 2.06 g of dicyclohexylcarbodiimide in 15 ml of dichloromethane. The mixture was stirred for 24 hours at room temperature, then filtered, and the filtrate was washed with 15 ml and 10 ml of water. The organic layer was dried, the solvent was removed on a rotary evaporator, and the residue was treated with aqueous NaHCO3 solution. The filtered aqueous solution was acidified to pH 3, and the mixture of the two tartaric acid ester diastereomers was extracted with dichloromethane, which was then concentrated, and the residue was suspended in acetone. Further processing of the reaction product is carried out in the same way as in Example 1. Analogously to the procedures in these examples, diastereomeric monoesters of (R,R)-0,0-diacetyltartaric acid with Metoprolol can also be obtained. Example 4. 15 g of a crystalline mass, constituting a mixture of diastereoisomers obtained according to Example 1, are placed in the Soxhlet apparatus and, while stirring, extracted several times with acetone. After about 10 runs with a solvent volume of about 300 ml, pure (R,R)-0,0-diacetyltartaric acid monoester with (S)-Propranolor crystallizes in the receiver (fraction II), while pure (R,R)-0,0-diacetyltartaric acid monoester with (R)-Propranolor (fraction I) remains in the Soxhlet apparatus. Fraction I: 7 g of (R,R)-diacetyltartaric acid monoester with (R)-Propranolor with a melting point of 196-198°C, with a rotation [cr]22546=13.5° (c = 0.405 in DMSO, i.e. in dimethyl sulfoxide) and an optical purity of more than 98%. Fraction II: 5 g of (R,R)-0,0-diacetyltartaric acid monoester with (S)-propranolor, melting point 176-177°C, rotation [cr]22546= + 33.0° (c = 0.98 in DMSO) and optical purity greater than 98%. 3 g of a mixture of fractions I and II remain in the acetone mother liquor. The NMR (nuclear magnetic resonance) data are consistent with the structure. Tartaric acid monoesters obtained during the reaction of (R,S)-Propranolor with (S,S)-O,O-diacetyltartaric anhydride instead of (R,R)-O,O-diacetyltartaric anhydride behave in a reverse way in their lipophilicity or extractability than in the previous treatment scheme, i.e. the residue in the Soxhlet apparatus cap is then the monoester of (S,S)-O,O-diacetyltartaric acid with (S)-Propranolor, while the more easily extractable fraction is the monoester of (S,S)-O,O-diacetyltartaric acid with (R)-Propranolor. Such inversion properties of diastereomeric compounds are generally valid and therefore also apply to other derivatives of (R,R)- or (S,S)-0,0-diacetyltartaric acid with alkanolamines. Due to the chemical structure of tartaric acid monoesters with alkanolamines, these esters occur as zwitterionic compounds or form inner salts. Hydrochlorides can also be prepared in non-aqueous aprotic solvents using strong acids, e.g. hydrochloric acid. Similarly, alkali metal or alkaline earth metal salts with a carboxyl group can be prepared by equivalent addition of alkali metal or alkaline earth metal hydroxides. Example V. Separation of the mixture of diastereomeric monoesters of (R,R)-0,0-diacetyltartaric acid with (R)- and (S)-Propranolor, obtained according to Example I, into enantiomers by means of thin-layer chromatography: thin-layer chromatography plates: silica gel called Kieselgel Si60 (product of Merck); eluent: acetone-isopropanol 1:1; development path: 8 cm R value = fraction II 0.41 alpha = 178 fraction I 0.23 Example VI. Analogously to the procedure in Example 1, Propranolol, Metoprolol, Acebutolol, Pindolol, Norpropranolol, and Nifenalol are reacted with (R,R)-0,0-dibenzoyltartaric anhydride. The obtained diastereomeric mixture of the given (R,R)-0,0-dibenzoyltartaric acid monoester is separated using reversed-phase high-pressure liquid chromatography (HPLC). Chromatographic separation system: column 250x4.6 mm internal diameter, filled with Spherisorb RP15, 5 µm adsorbent; Mobile phase: 2% acetic acid in redistilled water, adjusted with NH3 to pH = 3.7 - methanol 35-65. Table 1 k'R 4 1.38 0.88 1.88 1.63 0.63 k's 11 4.63 2.75 4.88 4.0 3.0 alpha = 2.75 3.35 3.13 2.59 2.5 4.8 Example VII. Analogously to the procedure in Example I, (R,S)-Propranolol is reacted with (R,R)-0,0-ditoluyltartaric anhydride and the diastereomeric ester mixture is separated by reversed-phase high-pressure liquid chromatography. Chromatographic separation system: column and mobile phase: as in Example VI k'R = 7,1,k's = 21,1,alpha = 2.98. Example VIII. Analogously to the procedure of Example 1, (R,S)-Propranolol is reacted with (R,R)-0,0-dimethyltartaric anhydride and separated by reversed-phase high-pressure liquid chromatography. Chromatographic separation system: column: as in Example 6; mobile phase: 2% ammonium acetate (pH = 3.7) - methanol/65-35 f k'R = 5.8, k's - 8.7, alpha = 1.5. Example 9 7 g (26 mmol) of basic (R,S)-methophore together with 4.4 g (27 mmol) of trichloroacetic acid are dissolved in 150 ml of 1,2-dichloroethane at room temperature. On a rotary evaporator, fractions of approximately 30 ml are azeotropically evaporated to achieve dehydration. To the remaining solution, 18 g (53 mmol) of (R,R)-dibenzoyltartaric anhydride is added and the solution is heated to approximately 80°C for 2 hours. After cooling, the excess reagent is filtered off, and the remaining solution is concentrated to dryness on a rotary evaporator. The residue is dissolved in 50 ml of acetone and 100 ml of 10% aqueous NaHCO 3 solution, whereupon a precipitate is formed, consisting of a mixture of tartaric acid monoesters with (R)- and (S)-methoprolol. After filtration on a suction filter and washing the precipitate with water, it is suspended in 100 ml of acetone and stirred for approximately 1 hour at room temperature. The precipitate is filtered again, yielding the above-named mixture of esters, the predominant fraction being the monoester of (R,R)-0,0-dibenzoyltartaric acid with (R)-methoprolol (fraction A). The corresponding (S)-methoprolol ester (fraction B) appears enriched in the acetone layer, which is concentrated to dryness. A total of 12.8 g (80% of theoretical yield) of fraction A together with fraction B is obtained. \ 5 g of the mixture of fractions A and B are dissolved in 20 ml of acetone and applied to a preparative (silica gel) column placed in acetone and eluted with acetone. Fraction B elutes before fraction A and thus fraction B can be isolated cleanly with high yield by means of fraction cleavage. Fraction B: 1.1 g of (R,R)-0,0-dibenzoyltartaric acid monoester with (S)-methoprolol with rotation [α]31546 = - 57.2° (c = 1 in CHCl3) and optical purity over 98%. The NMR data are consistent with the structure. Example X. According to examples I-III, (R,R)-0,0-dibenzoyltartaric anhydride is reacted with acebutolol. The obtained The diastereomeric mixture of esters is separated by reversed-phase high-pressure liquid chromatography. Chromatographic separation system: mobile phase: 2% acetic acid in redistilled water, adjusted with NH3 to pH = 3.7 - methanol/65-35; column: as in Example 6. k'R = 9.55, k's = 20.11, alpha = 2.1. Example 11. 18.15 g (0.05 mol) of basic (R,S)-Celiprolor together with 9 g (0.055 mol) of trichloroacetic acid are dissolved in 100 ml of dichloromethane at room temperature, and the solution is dried with MgSO4. To the solution, freed from the drying agent, are added 17 g (0.079 mol) of anhydride (R,R)-0,0-diacetyltartaric acid and stir the solution at room temperature. After a 90-minute reaction, 50 ml of saturated aqueous NaHCO3 solution was added to the organic solution and stirred vigorously. After separating the layers, this procedure was repeated again. The organic layer was dried with MgSO4, and then the dichloromethane was removed at room temperature under vacuum on a rotary evaporator. The residue was an amorphous solid, i.e., a mixture of (R,R)-0,0-diacetyltartaric acid monoesters with (R)- and (S)-Celiprolor (fraction A and fraction B). 29 g (approximately 90% of theoretical yield) of a mixture of diastereomers was obtained (with a low reagent content according to HPLC analysis). 10 g of the mixture of diastereomers of fractions A and B was dissolved in 50 ml acetone and injected into a preparative silica gel column filled with 500 g of Kieselgel Si60 silica gel (230-400 mesh). An acetone/isopropanol (1:1) mixture is used as the eluent. Fraction B elutes before fraction A, and this way it is possible to isolate pure fraction B with high yield by means of fraction cleavage. Yield: 2 g (40% of theoretical yield) of fraction B, i.e., the levorotatory monoester of (R,R)-0,0-diacetyltartaric acid with Celiprolor with a rotational coefficient [α] of 20 - - 41.3° (c = 1.0 in dichloromethane) and an optical purity of over 98%; 2.2 g of a mixed fraction and 2.4 g of fraction A contaminated with approximately 10% of the fraction B; 0.8 g (16% of theory) of fraction A, i.e. the dextrorotatory monoester of (R,R)-0,0,-diacetyltartaric acid with Celiprolor with a rotation [α]D20 = +54.5° (c = 1.0 in dichloromethane) and an optical purity of over 98%. Separation of the diastereomeric mixture by thin-layer chromatography: silica gel plates called Kieselgelplatte Si60 (product of Merck, Alufolie); eluent: isopropanol/acetone (1:1). Rf value = * ' alpha = 2.87 (development path = 10 cm). Fraction A 0.16 Spectroscopic data: 1H-NMR (DMSO-dG) tetramethylsilane (TMS) as internal standard, delta (ppm) Varian XL 200. CH tartaric acid: fraction A delta = 4.93 and 4.86 ppm (d, I = 7.5 Hz), fraction B delta = 5.50 and 5.20 ppm (d, I = 6.5 Hz). Example XII. 18.4 g (50 mmol) of basic (R,S)-Celiprolor together with 9 g (55 mmol) of trichloroacetic acid are dissolved in 100 ml of dichloromethane at room temperature. 146 074 9 This solution is then dried with MgSO4. After removal of the drying agent, 23.8 g (70 mmol) of (R,R)-0,0-dibenzoyltartaric anhydride are added to the solution and the solution is stirred at room temperature. After a 2-hour reaction, the excess reagent is filtered off under reduced pressure and the organic solution was shaken twice with 50 ml of saturated aqueous NaHCO3 solution and washed once with 50 ml of pure water. The remaining organic layer, after drying with MgSO 4 , was concentrated in vacuo on a rotary evaporator to dryness, leaving an amorphous solid residue consisting of the monoester of (R,R)-0,0-dibenzoyltartaric acid with (R)- or (S)-Celiprolor. 33 g (approximately 90% of theory) of a mixture of diastereoisomers of fraction I and fraction II (with negligible reagent content according to HPLC analysis) were obtained. 10 g of the mixture of diastereomers of fraction I and fraction II is dissolved in 50 ml of acetone, applied to a preparative silica gel column filled with 500 g of Kieselgel Si60 (230-400 mesh) and separated into fractions I and II using an eluent of acetone/isopropanol (18:1). Fraction II elutes before fraction I, and this method allows for the isolation of fraction II with high yield by fraction cleavage. Yield: 4.1 g (82% of theory) of fraction II, i.e. the levorotatory monoester of (R,R)-0,0-dibenzoyltartaric acid with Celliprolor, which is contaminated with about 10% of fraction I. From it, 3.5 g (70% of theory) of pure fraction II can be easily obtained by repeating the column separation under the same conditions. The pure fraction II obtained has a rotation [a]D2° = -62.6° (c= 1 in dichloromethane) and an optical purity of over 98%. Spectroscopic data: 1H-NMR (CDCl3) TMS as internal standard, delta (ppm); Varian XL 200. CU of (R,R)-tartaric acid: delta 5.56 and 5.45 ppm (d, 1 = 7 Hz). Separation of the diastereomeric mixture by thin-layer chromatography: Kieselgelplatte (Alufolie) Si60 silica gel plates (product of Merck); eluent: isopropanol/acetone (18:1). Rf value = fraction II 0.50 alpha =^ (development length = 11 cm) fraction I 0.09. Thus, by means of thin-layer chromatography, the fractions of column chromatography can be followed and controlled precisely and easily. Example XIII. 9 g (25 mmol) of basic (R,S)-Celiprolol together with 5 g (60 mmol) of trichloroacetic acid are dissolved in 100 ml of dichloromethane at room temperature. This solution is then dried with MgSO4. After removal of the drying agent, 9 g (80 mmol) of (S,S)-diacetyltartaric anhydride are added to the solution and the solution is stirred at room temperature. After a 90-minute reaction, the organic solution is shaken twice with 25 ml of saturated aqueous NaHCO3 solution and washed again with water. After drying the organic layer with MgSO 4 , it is concentrated to dryness in vacuo on a rotary evaporator, obtaining an amorphous powder consisting of the monoesters of (S,S)-O,O-diacetyltartaric acid with (R)- and (S)-Celiprolol (fraction a and fraction b). Yield: 13 g of a diastereomeric mixture (approximately 85% of theory). This diastereomeric mixture can be separated into its enantiomers by adsorption chromatography in the same way as in Example 11, but the order of separation is reversed. Fraction b, which elutes before fraction a, is now the dextrorotatory monoester of (S,S)-O,O-diacetyltartaric acid and Celiprolol. Fraction a is the corresponding isomer, namely the levorotatory monoester of (S,S)-0,0-diacetyltartaric acid and Celiprolol. Fraction B from Example 11 and fraction b in the present example (like fraction A and fraction a) behave enantiotropically, i.e. they exhibit the same chromatographic properties in non-chiral chromatographic systems. Chromatographic column separation and conditions: as in Example 11. Yield: 1.9 g (38% of theory) of fraction b, i.e. dextrorotatory monoester of (S,S)-0,0-diacetyltartaric acid with rotation [ct]d21 — 40.9° (c = 1.0 in dichloromethane).10 146 074 Separation of the mixture of diastereoisomers by thin-layer chromatography: silica gel plates called Kieselgelplatte (Alufolie) Si60 (product of Merck); eluent: isopropanol/acetone (1:1); development path = 11 cm. R value = fraction b °'46 alpha = 2.87 fraction a 0.16 Example XIV. From the β-blocking substances given below in Table 2, (R,R)-0,0-diethyltartaric acid monoesters are prepared analogously to the procedures in Examples 1-3, 11 and 12. Separation is carried out by reversed-phase high-pressure liquid chromatography (HPLC). Chromatographic separation system: column: as in Example 6; mobile phase: 0.1 M phosphoric acid, adjusted with aqueous NH3 solution to pH = 3.6 - methanol/50-50. Table 2 Ester of (R) or (S) Propranolol Metoprolol Celiprolol Pindolol k'R 5.45 1.81 0.62 0.86 k's 11.45- 3.43 1.0 1.57 alpha k's k'R 2.1 1.89 1.61 1.83 (R,R)- or optionally (S,S)-0,0-diacyl-, dialkyl- and -dibenzyl-tartaric acids or their anhydrides, which found use in various examples, were prepared according to methods known from the literature. Example XV. Analogously to the procedure in Example XI, basic (R,S)-Celiprolol is reacted with (R,R)-0,0-di(/3-dichlorovinyl)-tartaric anhydride. Separation is carried out by reversed-phase high-pressure liquid chromatography. Chromatographic separation system: column: as in Example VI; mobile phase: 0.1 M phosphoric acid, adjusted with aqueous NH3 solution to pH = 3.6 - methanol/40-60. k'R = 1.58, k's = 2.63, alpha = 1.66. The (R,R)-0,0-di//3-dichlorovinyl/-tartaric acid used was named (R,R)-0,0-di//3-dichloroethylavinyric acid by Shan and Alimchandani, J. Indian Chem. Soc. 11, 548 (1934). The acid used as a starting material was prepared analogously, isolated by extraction with ether and recrystallized from CH2Cl2/CHCl3, yielding a substance with a melting point of 125°C and a rotation [α]22546 = -49.1° (c=1.0 in methanol). Spectroscopic studies indicate that this is a vinyl compound. Example XVI. Analogously to Example I, (R,S)-Propranolol is reacted with (R,R)-O,O-diacetyltartaric acid, forming a mixture of isomers of the diastereomeric monoester of (R,R)-O,O-diacetyltartaric acid with (R)- and (S)-Propranolol. In the individual reactions, the solvents and acids listed in Table 3 below are used as protecting groups. Using ethyl ether as the solvent and then removing it gives a viscous residue which forms a melt at 60°C. In this alloy the reaction takes place with a yield of over 85% (compare the last example in Table 3). 146 074 11 (R.S.)-Propranolol, base or hydrochloride (quantity in mmol) 1 base (2) base (2) base T21 base (2) base (10) base (2) base (2) base (2) base (2) base (2) base (2) hydrochloride (2) hydrochloride (10) base (2) Table 3 Solvent Protecting group (quantity in ml) » acetone (3) acetone (3) acetonitrile (3) acetoniryl (3) tetrahydiofuran (15) dimethyl sulfoxide (3) dimethyl formamide (3) toluene (3) ethylene glycol dimethyl ether (3) ethyl acetate (3) N-methylpyrroli- 2-don-3 N-methylpyrroli- 2-don-3 dimethylformamide (3) ethyl ether (6) after firing melt at 60°C (quantity in mmol) 3 trichloroacetic acid (3) — trichloroacetic acid (3) — trichloroacetic acid 05) trichloroacetic acid (3) trichloroacetic acid (3) trichloroacetic acid (3) trichloroacetic acid (3) trichloroacetic acid (3) trichloroacetic acid (3) hydrochloric acid hydrochloric acid trichloroacetic acid (3) Reaction time (hours) 4 3 3 3 3 3 4 4 24 24 2 1 2 3 ^ i Reaction temperature (°C) 5 50 50 50 50 50 50 50 50 50 60 50 50 50 60 Yield (% of theoretical yield) 6 80 75 80 70 85 60 65 90 50 85 70 30 60 5 Example XVII. Similarly to Example 1, (R,S)-Propranool is reacted with the substituted (R,R0,0-tartaric anhydrides listed in Table 4 below, where 1,2-dichloroethane is used as a solvent and trichloroacetic acid is used as a protecting group. Separation of isomer mixtures of each of the formed diastereomeric monoesters of (R,R)-0,0-disubstituted tartaric acid with Propranolol is carried out analogously to Example 6 by means of reversed-phase high-pressure liquid chromatography (HPLC). Chromatographic separation system: column 250x4.0 mm in internal diameter, filled with adsorbent named Polygosil RPiE. 7 µm; mobile phase: a) 2% acetic acid in redistilled water, adjusted with NH3 to a pH of 3.7 - methanol/50:50 by volume; b) the same components as in a), but the ratio is 30:70 parts by volume. Table 4 Reagent Mobile phase k' R-Propranolol derivative k' S-Propranolol derivative k's a= k*R (R,R)-0,0-Diacetyltartaric anhydride (R,R)-0,0-Di- -3-chloropropionyltartaric anhydride (R,R)-0,0-Di- isovaleryltartaric anhydride < (R,R)-0,0-Di-phenylacetyltartaric anhydride (R,R)-0,0-Di- -trimethylacetyltartaric anhydride (R,R)-0,0-Di- -1H-tert.-butyltartaric anhydride (R,R)-0,0-Di- -benzoyltartaric anhydride a) a) b) b) b) b) b) 2.2 6.3 1.82 1.18 1.82 1.95 1.11 3.3 11 3.36 1.82 2.82 3.45 2.44 1.85 1.74 1.85 1.54 1.55 1.77 2.212 146 074 The (R,R)-0,0-diacyltartaric anhydrides used in the reaction are prepared analogously to (R,R)-0,0-diacetyltartaric anhydride and they show the properties given in Table 5. Table 5 (R,R)-0,0-di-3-chloropropionyltartaric anhydride (R,R)-0,0-diisovaleryltartaric anhydride (R,R)-0,0-di-phenylacetyltartaric anhydride (R,R)-0,0-di-trimethylacetyltartaric anhydride [α]25546=+81.7° (c= 1.01 in dichloroethane) [α]25546=+45° (c = 0.534 in dichloroethane) [α]25546=+51.2° (c = 0.605 in dichloroethane) [α]25546=+39.7° (c = 0.494 in dichloroethane) (R,R)-0,0-di-tert.-butyltartaric anhydride is prepared as described below. 10 g of (R,R)-dimethyl tartrate in 140 ml of diethylene glycol dimethyl ether in a pressure bottle was treated with 40 ml of isobutene and 3 ml of concentrated sulfuric acid and kept at room temperature with shaking for 48 hours. After neutralization with dilute potassium hydroxide solution, the mixture was shaken with ether and finally recrystallized from petroleum ether. 5 g of the bis-ether thus obtained (mp. 68°C) was heated in 80 ml of 50% methyl sulfoxide with 3 g of potassium hydroxide solution for 3 hours at 100°C. After acidification, it is shaken with ethyl ether, washed with water, and after drying, treated with an equimolar amount of dicyclohexylcarbodiimide. After stirring for 2 hours at room temperature, the dicyclohexylurea formed is separated, the ether is distilled off in vacuo, and the residue is recrystallized from n-hexane, yielding pure (R,R)-0,0-di-tert.-butyltartaric anhydride with a rotation [cr]25546 = + 107.3° (c = 0.996 in dichloroethane). Claims 1. A method for preparing new, optically pure tartaric acid monoesters with optically active alkanolamines of the general formula I, wherein A is a nitrophenyl, naphthyloxymethyl or indolyloxymethyl group or a substituted phenoxymethyl group of the formula V, wherein R3 is a methoxyethyl group or an Acyl-NH- group, wherein Acyl is a lower alkanoyl radical with at most 4 carbon atoms or a dialkylcarbamoyl radical with 1 or 2 carbon atoms in each alkyl substituent, and R4 is a hydrogen atom or an acetyl radical, R2 is a hydrogen atom or a branched alkyl radical with 3 or 4 carbon atoms, R1 is a radical of disubstituted (R,R)- or (S,S)-tartaric acid of the general formula II, wherein R5 is a straight-chain or a branched alkyl radical with 1-4 carbon atoms, a benzyl radical, optionally substituted with chlorine, a straight-chain or branched alkanoyl radical with 1-5 carbon atoms, a phenylacetyl, benzoyl, toluoyl or β, β-dichlorovinyl radical, and their salts with acids or bases, characterized in that the mixture of enantiomers of the general formula 3, wherein A and R2 have the meaning given above, is reacted in the melt or in an aprotic solvent with a disubstituted (R,R)- or (S,S)- tartaric acid of the general formula 4, wherein R5 has the meaning given above, or with its anhydride, provided that the reaction with the free acid is carried out in the presence of a condensing agent, after which the resulting mixture of pairs of isomers of tartaric acid monoesters of the formula 1 is isolated, and then the obtained racemic mixture is separated into enantiomers, which are optionally converted into salts. 2. The method according to claim 1, characterized in that the primary or secondary amino group in the compounds of formula 3 is protected before the reaction, and after the reaction with disubstituted tartaric acid of formula 4 or with its anhydride, this protecting group is cleaved. 146 074 13 3. The method according to claim 2, characterized in that the protection of the amino group is carried out by reacting the compound of formula 3 with an inorganic or organic acid forming an ion pair bond with the amino group that only slightly dissociates under esterification conditions, and after the esterification, this protecting group is cleaved by alkalization. 4. The method according to claim 5. The method according to claim 1, 2, 3 or 4, wherein the esterification is carried out in an anhydrous aprotic solvent at a temperature from room temperature to 90°C. 6. The method according to claim 5, wherein the aprotic solvent is dichloromethane, 1,2-dichloroethane, acetone, acetonitrile, toluene, dimethyl sulfoxide, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or N-methylpyrrolidone-2. 7. The method according to claim 1, 2, 3 or 4, wherein the esterification is carried out in an anhydrous aprotic solvent at a temperature from room temperature to 90°C. 8. A process according to claim 7, characterized in that the separation is carried out by adsorption chromatography with organic eluents in silica gel or alumina columns. 9. A process according to claim 8, characterized in that a mixture of acetone and isopropanol is used as the eluent. 10. A process according to claim 7, characterized in that the separation is carried out by reversed-phase high-pressure liquid chromatography. 12. The method according to claim 10, characterized in that a methanol-buffer solution system is used as the mobile phase. 13. The method according to claim 1, characterized in that a compound of formula 3 is used, wherein A is a naphthyloxymethyl group, and R2 is an isopropyl radical or a hydrogen atom. 14. The method according to claim 1, characterized in that a compound of formula 3 is used, wherein A is a group of formula 5, wherein R3 is a (C2Hs)2N-CO-NH- group, and R4 is an acetyl radical, and R2 is a tert-butyl radical. 15. The method according to claim 1, characterized in that a compound of formula 3 is used, wherein A is a group of formula 5, wherein R3 is a methoxyethyl group, and R4 is a hydrogen atom, and R2 is an isopropyl radical. 15. A method according to claim 1, characterized in that a compound of formula 3 is used, wherein A is a p-nitrophenyl group and R2 is an isopropyl radical. 146 074 A-CH-CH2-NH-R2 ORn Formula 1 HOOC- CH (0R5)-Ch(0R5C0- tyzor 2 A-CH-CH2-NH-R2 OH Formula 3 HOOC- CH (0R5) - CH (OR5)-COOH Formula 4 R3^yo-cH2- R4 Formula 5 Printing Studio of the Polish Patent Office. 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Claims (1)

1.